High prevalence of oncogenic MYD88 and CD79B mutations in diffuse large B-cell lymphomas presenting at immune-privileged sites.

Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract

Activating mutations in CD79 and MYD88 have recently been found in a subset of diffuse large B-cell lymphoma (DLBCL), identifying B-cell receptor and MYD88 signalling as potential therapeutic targets for personalized treatment. Here, we report the prevalence of CD79B and MYD88 mutations and their relation to established clinical, phenotypic and molecular parameters in a large panel of DLBCLs. We show that these mutations often coexist and demonstrate that their presence is almost mutually exclusive with translocations of BCL2, BCL6 and cMYC, or Epstein-Bar virus infection. Intriguingly, MYD88 mutations were by far most prevalent in immune-privileged site-associated DLBCL (IP-DLBCL), presenting in central nervous system (75%) or testis (71%) and relatively uncommon in nodal (17%) and gastrointestinal tract lymphomas (11%). Our results suggest that MYD88 and CD79B mutations are important drivers of IP-DLBCLs and endow lymphoma-initiating cells with tissue-specific homing properties or a growth advantage in these barrier-protected tissues.

Prevalence of MYD88 and CD79B mutations in DLBCL. (a) Percentage of DLBCL with MYD88 and/or CD79B mutations in all DLBCLs tested (n=177). (b) Percentage of tumours with MYD88 and/or CD79B mutations in ABC-type and germinal centre B-cell (GCB)-type DLBCL. Prevalence of MYD88 and CD79 mutations in ABC DLBCL was significantly different from that in GC DLBCL (**P<0.01; ***P<0.001 by Fisher's exact test). (c) Overlap of MYD88 and CD79B mutations with other recurrent oncogenic events in DLBCL.

Prevalence of mutations in MYD88 and CD79B by tumour localization. Percentage of ABC DLBCL with MYD88 and/or CD79B mutations at different anatomical sites. Prevalence of MYD88 mutations in central nervous system (CNS) and testis was significantly different from that in the lymph node and gastrointestinal (GI) tract (***P<0.001 by Fisher's exact test).